The goal of this project is to investigate the phenomenon of novelty- induced facilitation of long-term potentiation (LTP). LTP is a mechanism of synaptic plasticity that may underlie certain forms of learning. LTP induced in medial perforant path projections to the dentate gyrus induce din awake, freely-moving animals persists from 3-5 days following a single stimulation session 6/24/51. However, if LTP is induced during the first 5-20 minute period of exploration of a novel environment, then both the probability of LTP induction and the magnitude of LTP are increased Further, LTP induced in a novel environment persists for an average of 10 days following a single stimulation session. These effects are independent from both brain temperature and movement, as well as theta rhythm occurring during exploration. Importantly, repeated exposure to the same novel environment produces progressively less facilitation of LTP. By contrast, LTP induced in the home cage is consistent in magnitude and time course with repeated induction. Thus, it appears familiarity with the environment reduces the novelty facilitation effect. These data indicate that processes(s) associated with the detection of novelty and/or arousal associated with exploratory behaviors facilitate LTP induction and longevity. In these studies, we will address behavioral, pharmacological and anatomical aspects of novelty-induced facilitation. The studies in Specific Aim 1 will determine the time course of facilitation, and assess the longevity of facilitation following placement in a novel environment. We will also assess whether familiarity underlies the decrement observed with repeated exposures to the same novel environment by determining if returning the animal to a familiar environment rapidly reverses the effect of novelty-induced facilitation, and if distinct novel environments lead to re-emergence of LTP facilitation. In Specific Aim 2, pharmacological methods will be used to determine if neuromodulatory systems that are active during exploration and arousal contribute novelty-induced facilitation of LTP induction and maintenance. We will investigate the contribution of cholinergic, adrenergic and opiodergic neuromodulatory systems to this facilitation effect, each of which are active during exploration. The studies of Specific Aim 3, we will determine if novel environments similarly alter LTP induction and LTP maintenance in Schaffer-CA1 projections, commissural-CA3 proje3ctions, and direct perforant path projections to hippocampal area CA3. These studies will allow us to determine the effects of novelty and neuromodulatory systems on LTP induction in the primary synaptic systems of the hippocampus, and address the role of neuromodulators and novelty detection in processes of memory storage that may be relevant to both memory disorders and current models of hippocampal information processing.